One of the major issues in asthma is the lack of adherence to inhaled therapies, which is observed in nearly 50% of patients1. Poor asthma treatment compliance is associated with higher morbidity and mortality and with greater use of health services2.

Many studies have attempted to identify which factors are associated with nonadherence. Noncompliance has been related to the patient's own characteristics (e.g., age, sex, sociocultural level, poor experiences with previous treatments, depression, lack of social support), complexity of the inhalation regimen, peculiarities of the inhaler devices and the type of inhaled agent3,4.

To measure adherence to inhalers, direct and indirect methods are employed. Direct methods, which include electronic monitoring and drug levels, are based on the quantification of a drug, its metabolites or a tracer substance in a biological fluid (blood, urine, saliva or skin). These methods are objective, specific, accurate and reliable, but also expensive, complex and can only be used with some drugs3. In contrast to direct methods, indirect ones, such as obtaining clinical information by anamnesis, are economic and can be employed for all inhalers. However, they tend to provide erratic results5. Accordingly, in clinical practice, use of validated questionnaires with acceptable reliability is recommended. Therefore, the Spanish Society of Pneumology and Thoracic Surgery has developed the Test of Adherence to Inhalers (TAI) questionnaire to assess patient compliance when receiving inhalers in daily clinical practice. As mentioned previously, however, self-report questionnaires tend to overestimate compliance6, so that the use of concurrent methods to measure adherence, such as medication withdrawal in pharmacies obtained from pharmacy refill data (PRD), are recommended when using questionnaires6–8. According to this strategy, and due to the simplicity, low cost and acceptable reliability of both methods, the Global Initiative for Asthma (GINA) and the Spanish Guideline on the Management of Asthma propose using them concurrently6,7.

Previous studies that have evaluated the degree of inhaler compliance using the TAI questionnaire and PRD in patients diagnosed with asthma, analysed all severities of asthma together and have not been focused on patients receiving specific biologic treatments to control asthma2,9. The use of anti-interleukin-5 (anti-IL-5) therapy agents in the treatment of asthma has been associated with improvements in respiratory symptoms, lung function and control of the disease10–14. Therefore, we suspect that the high efficacy of anti-IL-5 biologics in controlling asthma might predispose patients to abandon treatment with inhalers and, as a consequence, to reduce the adherence to inhaled therapy. For this reason, we aimed to determine the prevalence of nonadherence to inhaler medication based on the TAI questionnaire and PRD in patients with severe asthma treated with anti-IL-5 biologics and to define the degree of concordance between these two measures.

To our knowledge, this is the first study that analyses the degree of compliance using two methods, PRD and the TAI questionnaire, in patients diagnosed with severe asthma and treated with anti-IL-5 biologics. Our results show a higher percentage of nonadherent patients when combining both methods. Likewise, we have detected that PRD identify a higher percentage of nonadherent patients compared with the TAI questionnaire. Finally, the results of both methods are poorly correlated, a finding in line with the results reported by Plaza et al.9.

When treating asthma, it is important to use long-term control medications to achieve and maintain control of the disease, but it is also necessary that patients follow the recommendations provided. With respect to severe asthma, its treatment frequently requires polymedication; thus, deficient adherence increases the risk of poorer control of the disease, leading to more exacerbations and higher morbidity and mortality rates18,19. In developed countries, adherence to treatment in chronic diseases is approximately 50%20, and it tends to be lower in asthma, where it ranges from 22% to 78%6. In this context, we have found a high prevalence of nonadherence to inhalers in patients with severe asthma on therapy with anti-IL-5 biologics. Thus, we have identified a higher percentage of nonadherence (58.5%) compared with other studies2,9,21,22. One explanation could be that, given our population was included from a severe asthma unit and all of them were being treated with anti-IL-5 biologics, we were unable to find any research with the same study population with which to compare them. Thus, anti-IL-5 biologics, unlike inhalers, have the advantage of being administered monthly or bimonthly. Given that their use is associated with an important improvement in respiratory symptoms, patients have a higher risk of abandoning their treatment with inhalers and, as a consequence, of reducing their adherence to inhaled therapy. In fact, the multidisciplinary consensus Delphi study23 supports that improvement of symptoms in asthma predisposes patients to nonadherence because patients believe that treatment becomes unnecessary24. Various studies have shown a relationship between beliefs about asthma and adherence to preventive therapy, especially in those patients who consider that asthma is an episodic rather than a chronic disease, and that therapy is necessary only during exacerbations25.

Self-report questionnaires are commonly used to measure adherence due to their low cost, acceptable reliability and the short time required to complete them (less than 10 minutes for the TAI questionnaire)16,17. Thus, the TAI questionnaire was specifically designed for inhalers, and it also assesses the type of noncompliance16,17. On the other hand, PRD makes it possible to calculate adherence by comparing the prescription made through the electronic prescription system with the medication dispensed in pharmacies in a given period of time. Previous studies have reported that low nonadherence rates detected by the PRD are related to the low cost of inhalers in Spain (which has universal health care coverage)9. Nevertheless, our results highlight that nonadherence is higher when assessed by PRD than by TAI questionnaire. Furthermore, we suspect that this rate of nonadherence obtained when using PRD could even be underestimated, given that patients could continue getting inhalers from the pharmacy (adherence obtained from the PRD) without taking them (adherence obtained from the TAI questionnaire). In previous studies2,9, the TAI questionnaire identified more nonadherent patients than the PRD, whereas in our population it is the other way around. This difference could be explained by multiple factors. First, the use of anti-IL-5 biologics is associated with a considerable improvement of respiratory symptoms10–14; second, the belief that inhalers are necessary only during exacerbations25,26. Both factors contribute to nonadherence to inhalers and consequently nonwithdrawal at the pharmacy.

We have shown poorer agreement between methods. Llano et al.2, who also used the TAI questionnaire and PRD to estimate the adherence to inhalers in patients with asthma, but not in patients with severe asthma who are on anti-IL-5 biologics, reported a moderate agreement between methods. Nevertheless, Plaza et al.9 reported that these methods are poorly correlated, a finding consistent with our results (k = 0.137). This low correlation supports their concomitant use in clinical practice as is recommended by clinical guidelines6,7.

This study has potential strengths. First, as far as we know, this is the first study conducted in a population treated with biologics. Second, our results agree with previous studies9,27 and guidelines6,7 that support the concomitant use of two methods to evaluate adherence in asthma. We show that this recommendation could be extended to patients with severe asthma treated with anti-IL-5 biologics. Third, although it might appear that our sample is small in relative terms, we have included a larger number of patients than previous studies2,9, given that severe asthma affects approximately 4%28,29 of the population worldwide, and not all of them use biologics. Even though lung function test results were not analysed, they were not necessary for our objective.

As limitations of the study, we consider first that none of the methods used to assess adherence is considered the gold standard. Another limitation of our study is the design, as it is retrospective, monocentric and lacks of a control group (not treated with anti-IL-5 biologics). Although we have included comorbidities as a variable in our study, because they also affect adherence to medications, other factors might also be involved in adherence to inhalers and have not been considered such as age group, number of medications, duration of asthma, health literacy or number of exacerbations.

In conclusion, our results highlight the high prevalence of nonadherence to inhalers in severe asthma treated with biologics. Also, the agreement between indirect methods that evaluate adherence is low; therefore, it is plausible to use them concurrently in clinical practice1.

No funding.

No conflict of interests.